title: Design of a phase I clinical trial to evaluate intratumoral delivery of ErbB-targeted chimeric antigen receptor T-cells in locally advanced or recurrent head and neck cancer.
abstract: Despite several advances, 5-year survival in patients with head and neck squamous cell carcinoma (HNSCC) remains unchanged at only 50%. The commonest cause of death is locally advanced/recurrent disease. Consequently, there is an unmet need for new approaches to improve local control in HNSCC. T4 immunotherapy is an autologous cell therapy in which peripheral blood T-cells are genetically engineered using a retroviral vector to coexpress two chimeric receptors: (i) T1E28z is a chimeric antigen receptor that engages multiple ErbB dimers that are commonly upregulated in HNSCC; (ii) 4αβ is a chimeric cytokine receptor that converts the weak mitogenic stimulus provided by interleukin (IL)-4 into a strong and selective growth signal, allowing preferential expansion and enrichment of T4(+) T-cells ex vivo. T4 immunotherapy exerts antitumor activity against HNSCC cell lines and tumors in vivo, without significant toxicity. Human T4(+) T-cells also engage mouse ErbB receptors, permitting safety testing in SCID Beige mice. Severe toxicity caused by cytokine release syndrome ensues when human T4(+) T-cells are administered at high doses to mice, particularly with advanced tumor burdens. However, such toxicity is not required for efficacy and is never seen if T-cells are administered by the intratumoral route. To exploit this, we have designed a first-in-man clinical trial in which T4(+) T-cells are administered to patients with locally advanced/recurrent HNSCC. Cells will be administered at a single sitting to multiple sites around the viable tumor circumference. A 3+3 dose escalation design will be used, starting at 10(7) cells (cohort 1), escalating to 10(9) cells (cohort 5). If maximum tolerated dose remains undefined, cohorts 6/7 will receive either low- or high-dose cyclophosphamide before 10(9) T4(+) T-cells. A panel of routine/in-house assays and imaging techniques will be used to monitor safety, efficacy, perturbation of endogenous antitumor immunity, immunogenicity, and T-cell trafficking.
authors.affiliation: 1 Department of Research Oncology, King's Health Partners Integrated Cancer Centre , King's College London, London SE1 9RT, United Kingdom .
authors.forename: May C I
authors.initials: MC
authors.lastname: van Schalkwyk
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Papa
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Jeannon
authors.forename: Teresa
authors.initials: T
authors.lastname: Guerrero Urbano
authors.forename: James F
authors.initials: JF
authors.lastname: Spicer
authors.forename: John
authors.initials: J
authors.lastname: Maher
mesh_terms: D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D005260:Female; D018815:Genes, erbB; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D008297:Male; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012107:Research Design; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation
chemical_list: D011946:Receptors, Antigen; D018121:Receptors, Cytokine; D011994:Recombinant Proteins